tbuckley/cabot-search huggingface dataset:
A Diabetes Genetic Risk Score Is Associated With All-Cause Dementia and Clinically Diagnosed Vascular Dementia in the Million Veteran Program
Authors: Elizabeth M. Litkowski, Mark W. Logue, Rui Zhang, Brian R. Charest, Ethan M. Lange, John E. Hokanson, Julie A. Lynch, Marijana Vujkovic, Lawrence S. Phillips, Leslie A. Lange, Richard L. Hauger, Sridharan Raghavan
Journal: Diabetes Care (2022)

Diabetes and dementia are diseases of high health care burden worldwide, and studies have shown that diabetes is associated with an increased relative risk of dementia. We set out to examine whether type 2 diabetes-associated genetic variants were associated with dementia and whether they differed by race/ethnicity or clinical dementia diagnosis.We evaluated associations of two type 2 diabetes genetic risk scores (GRS and GRS-nonAPOE: a score without rs429358, a variant associated with Alzheimer disease [AD]) with three classifications of clinical dementia diagnoses in the Million Veteran Program (MVP): all-cause dementia, vascular dementia (VaD), and AD. We conducted our analysis stratified by European (EUR), African (AFR), and Hispanic (HIS) races/ethnicities.In EUR, we found associations of the GRS with all-cause dementia (odds ratio [OR] 1.06, P = 1.60e-07) and clinically diagnosed VaD (OR 1.12, P = 5.2e-05) but not with clinically diagnosed AD (OR 1.02, P = 0.43). The GRS was not associated with any dementia outcome in AFR or HIS. When testing with GRS-nonAPOE, we found that effect size estimates in EUR increased and P values decreased for all-cause dementia (OR 1.08, P = 2.6e-12), for VaD (OR 1.14, P = 7.2e-07), and for AD (OR 1.06, P = 0.018). For AFR, the association of GRS-nonAPOE and clinically diagnosed VaD (OR 1.15, P = 0.016) was statistically significant. There were no significant findings for HIS.We found evidence suggesting shared genetic pathogenesis of diabetes with all-cause dementia and clinically diagnosed VaD.
An Alternatively Spliced p62 Isoform Confers Resistance to Chemotherapy in Breast Cancer
Authors: Qianying Guo, Hao Wang, Jiahao Duan, Wenwu Luo, Rongrong Zhao, Yuting Shen, Bijun Wang, Siqi Tao, Yi Sun, Qian Ye, Xiaomin Bi, Hui Yuan, Qiang Wu, Peter E. Lobie, Tao Zhu, Sheng Tan, Xing Huang, Zhengsheng Wu
Journal: Cancer Research (2022)

Abstract Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathologic complete response. In this study, we report a novel p62 mRNA isoform with a short 3′-UTR (untranslated region; p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3′-RACE, and Northern blot analysis. In vitro and in vivo, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3′-UTR (p62-LU, 1,485-nt). Mechanistically, cleavage and polyadenylation specific factor 1 (CPSF1) modulated the 3′-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p–mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy. Significance: Resistance to NAC in breast cancer is driven by a novel p62 mRNA isoform that escapes miRNA-mediated repression and leads to increased p62 protein expression.
Management of Orofacial Manifestations of Juvenile Idiopathic Arthritis: Interdisciplinary <scp>Consensus‐Based</scp> Recommendations
Authors: Peter Stoustrup, Cory M. Resnick, Shelly Abramowicz, Thomas K. Pedersen, Ambra Michelotti, Annelise Küseler, Bernd Koos, Carlalberta Verna, Ellen B. Nordal, Eric J. Granquist, Josefine Mareile Halbig, Kasper D. Kristensen, Leonard B. Kaban, Linda Z. Arvidsson, Lynn Spiegel, Matthew L. Stoll, Melissa A. Lerman, Mia Glerup, Patrizia Defabianis, Paula Frid, Per Alstergren, Randy Q. Cron, Sarah Ringold, Sven Erik Nørholt, Timo Peltomaki, Tore A. Larheim, Troels Herlin, Zachary S. Peacock, Christian J. Kellenberger, Marinka Twilt
Journal: Arthritis & Rheumatology (2022)

Involvement of the temporomandibular joint (TMJ) is common in juvenile idiopathic arthritis (JIA). TMJ arthritis can lead to orofacial symptoms, orofacial dysfunction, and dentofacial deformity with negative impact on quality of life. Management involves interdisciplinary collaboration. No current recommendations exist to guide clinical management. We undertook this study to develop consensus-based interdisciplinary recommendations for management of orofacial manifestations of JIA, and to create a future research agenda related to management of TMJ arthritis in children with JIA. Recommendations were developed using online surveying of relevant stakeholders, systematic literature review, evidence-informed generation of recommendations during 2 consensus meetings, and Delphi study iterations involving external experts. The process included disciplines involved in the care of orofacial manifestations of JIA: pediatric rheumatology, radiology, orthodontics, oral and maxillofacial surgery, orofacial pain specialists, and pediatric dentistry. Recommendations were accepted if agreement was >80% during a final Delphi study. Three overarching management principles and 12 recommendations for interdisciplinary management of orofacial manifestations of JIA were outlined. The 12 recommendations pertained to diagnosis (n = 4), treatment of TMJ arthritis (active TMJ inflammation) (n = 2), treatment of TMJ dysfunction and symptoms (n = 3), treatment of arthritis-related dentofacial deformity (n = 2), and other aspects related to JIA (n = 1). Additionally, a future interdisciplinary research agenda was developed. These are the first interdisciplinary recommendations to guide clinical management of TMJ JIA. The 3 overarching principles and 12 recommendations fill an important gap in current clinical practice. They emphasize the importance of an interdisciplinary approach to diagnosis and management of orofacial manifestations of JIA.
Impact of a Novel Diabetes Prevention Intervention for Early Slow Weight Loss Responders Among Adults With Prediabetes: An Adaptive Trial
Authors: Carla K. Miller, Haikady N. Nagaraja, Jennifer Cheavens, Kentaro Fujita, Sophie Lazarus
Journal: Diabetes Care (2022)

Some people are slower to respond during lifestyle interventions. An adaptive "rescue" intervention may improve outcomes among slow responders. The impact of a worksite rescue intervention for early slow responders was evaluated.Employees ≥21 years old with prediabetes were stratified to intervention using a 2.5% weight loss (%WL) threshold at week 5. Outcomes were assessed at baseline and at 4 months using mixed-effect and linear regression models.Significant improvement occurred in mean %WL, glycemia, total cholesterol, and triglycerides in the standard compared with the adaptive (Group Lifestyle Balance Plus [GLB+]) intervention (all P≤ 0.01). However, GLB+ participants also experienced a significant reduction in %WL and glycemia (all P < 0.01). The %WL at week 5 significantly predicted %WL at 4 months (P < 0.0001). The between-group difference of 4-month %WL was not significant for someone achieving 2.5%WL at week 5.Diabetes prevention programs should consider weight loss success following 1 month of treatment and offer a rescue intervention to early slow weight loss responders.
Natural Dual‐Crosslinking Bioadhesive Hydrogel for Corneal Regeneration in Large‐Size Defects
Authors: Long Zhao, Zhen Shi, Xiuli Sun, Yaoyao Yu, Xin Wang, Hongwei Wang, Tan Li, Hengrui Zhang, Xiaoyu Zhang, Fuyan Wang, Xia Qi, Rui Cao, Lixin Xie, Qingjun Zhou, Weiyun Shi
Journal: Advanced Healthcare Materials (2022)

Abstract Corneal injectable hydrogels represent a promising alternative to alleviate donor shortage and simplify traditional surgeries. However, most hydrogels focus on repairing focal corneal defects (≤3.5 mm) and leave many clinical requirements unmet. Herein, a novel ion‐activated bioadhesive hydrogel (IonBAH) is designed and its long‐term performance of repairing large corneal defects (6 mm) is evaluated in rabbits for 6 months. The IonBAH is a dual‐network hydrogel composed of natural corneal extracellular matrix and peptide‐modified alginate, which enables its desirable transparency and biocompatibility, tunable mechanics, and robust adhesion. Moreover, the IonBAH maintains the secretory phenotype of quiescent keratocytes, while preventing their myofibroblastic differentiation in vitro. Upon application in situ, it rapidly seals the 6 mm corneal defect and forms normal curvature through the coverage of a contact lens impregnated with calcium ions. During the 6 months follow‐up, the IonBAH promotes rapid regeneration of corneal epithelium, stroma, and nerves with restored transparency, equivalent to the outcome of donor corneal transplantation. In addition, the suitability of IonBAH as an adhesive and patch for various clinical requirements are also evaluated with a pleasing outcome. Collectively, IonBAH may provide a clinically applicable scaffold for corneal surgeries, especially in large defect repair.
Developmental Deconvolution for Classification of Cancer Origin
Authors: Enrico Moiso, Alexander Farahani, Hetal D. Marble, Austin Hendricks, Samuel Mildrum, Stuart Levine, Jochen K. Lennerz, Salil Garg
Journal: Cancer Discovery (2022)

Cancer is partly a developmental disease, with malignancies named based on cell or tissue of origin. However, a systematic atlas of tumor origins is lacking. Here we map the single-cell organogenesis of 56 developmental trajectories to the transcriptomes of over 10,000 tumors across 33 cancer types. We deconvolute tumor transcriptomes into signals for individual developmental trajectories. Using these signals as inputs, we construct a developmental multilayer perceptron (D-MLP) classifier that outputs cancer origin. D-MLP (ROC-AUC: 0.974 for top prediction) outperforms benchmark classifiers. We analyze tumors from patients with cancer of unknown primary (CUP), selecting the most difficult cases in which extensive multimodal workup yielded no definitive tumor type. Interestingly, CUPs form groups distinguished by developmental trajectories, and classification reveals diagnosis for patient tumors. Our results provide an atlas of tumor developmental origins, provide a tool for diagnostic pathology, and suggest developmental classification may be a useful approach for patient tumors. Here we map the developmental trajectories of tumors. We deconvolute tumor transcriptomes into signals for mammalian developmental programs and use this information to construct a deep learning classifier that outputs tumor type. We apply the classifier to CUP and reveal the developmental origins of patient tumors. See related commentary by Wang, p. 2498. This article is highlighted in the In This Issue feature, p. 2483.
Phase 2 Study of the PD-1 Inhibitor Serplulimab plus the Bevacizumab Biosimilar HLX04 in Patients with Previously Treated Advanced Hepatocellular Carcinoma
Authors: Zhenggang Ren, Guoliang Shao, Jie Shen, Li Zhang, Xu Zhu, Weijia Fang, Guoping Sun, Yuxian Bai, Jianbing Wu, Lianxin Liu, Yuan Yuan, Jingdong Zhang, Zhen Li, Ling Zhang, Tao Yin, Jincai Wu, Xiaoli Hou, Qingyu Wang, Jun Zhu, Jia Fan
Journal: Liver Cancer (2022)

Introduction: Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. Methods: In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. Results: As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9–54.3) in group A and 14.3% (95% CI, 3.0–36.3) in group B. Median duration of response was not reached (95% CI, 3.3–not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9–NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4–5.5) and 4.1 months (95% CI, 1.5–NE), and median overall survival was 11.6 months (95% CI, 6.4–NE) and 14.3 months (95% CI, 8.2–NE) in groups A and B, respectively. Conclusion: Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.
Call for action: expanding global access to hereditary cancer genetic testing
Authors: Brittany Bychkovsky, Huma Q Rana, Foluso Ademuyiwa, Jennifer Plichta, Karen Anderson, Angélica Nogueira-Rodrigues, Cesar A Santa-Maria, Lan G Coffman, Carol Marquez, Arunangshu Das, Alphonse Taghian, Diane R Koeller, Renata L Sandoval, Ben Ho Park, Don S Dizon
Journal: The Lancet Oncology (2022)
The QT interval prolongation potential of anticancer and supportive drugs: a comprehensive overview
Authors: Eline L Giraud, Kaylee R M Ferrier, Nienke A G Lankheet, Ingrid M E Desar, Neeltje Steeghs, Rypko J Beukema, Nielka P van Erp, Elise J Smolders
Journal: The Lancet Oncology (2022)
Development of an international standard set of outcome measures for patients with venous thromboembolism: an International Consortium for Health Outcomes Measurement consensus recommendation
Authors: Adam M Gwozdz, Cindy M M de Jong, Luz Sousa Fialho, Theerawich Likitabhorn, Frieda Sossi, Paula Blancarte Jaber, Anette Arbjerg Højen, Juan I Arcelus, William R Auger, Cihan Ay, Stefano Barco, Marcelo B Gazzana, Julie Bayley, Laurent Bertoletti, Arina ten Cate-Hoek, Alexander T Cohen, Jean M Connors, Jean-Philippe Galanaud, Nicos Labropoulos, Nicole Langlois, Mark H Meissner, Simon Noble, Esther J Nossent, Paula Ponce de León Lovatón, Helia Robert-Ebadi, Rachel P Rosovsky, Noa Smolenaars, Mark Toshner, Cécile Tromeur, Kang-Ling Wang, Eli Westerlund, Kerstin de Wit, Stephen A Black, Frederikus A Klok
Journal: The Lancet Haematology (2022)
Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial
Authors: Régis Peffault de Latour, Jeff Szer, Ilene C Weitz, Alexander Röth, Britta Höchsmann, Jens Panse, Kensuke Usuki, Morag Griffin, Jean-Jacques Kiladjian, Carlos M de Castro, Hisakazu Nishimori, Temitayo Ajayi, Mohammed Al-Adhami, Pascal Deschatelets, Cedric Francois, Federico Grossi, Antonio M Risitano, Peter Hillmen
Journal: The Lancet Haematology (2022)
CNS prophylaxis for diffuse large B-cell lymphoma
Authors: Toby A Eyre, Kerry J Savage, Chan Y Cheah, Tarec C El-Galaly, Katharine L Lewis, Pamela McKay, Matthew R Wilson, Andrew M Evens, Sabela Bobillo, Diego Villa, Matthew J Maurer, Kate Cwynarski, Andrés J M Ferreri
Journal: The Lancet Oncology (2022)
A community mobilisation intervention to improve engagement in HIV testing, linkage to care, and retention in care in South Africa: a cluster-randomised controlled trial
Authors: Sheri A Lippman, Audrey Pettifor, Mi-Suk Kang Dufour, Chodziwadziwa Whiteson Kabudula, Rhian Twine, Dean Peacock, Rhandzekile Mathebula, Aimée Julien, Rebecca West, Torsten B Neilands, Ryan Wagner, Ann Gottert, F Xavier Gómez-Olivé, Dumisani Rebombo, Nicole Haberland, Julie Pulerwitz, Louis Pappie Majuba, Stephen Tollman, Kathleen Kahn
Journal: The Lancet HIV (2022)

Community mobilisation, engaging communities in a process to collectively enact change, could improve HIV testing and care engagement. In South Africa, current rates fall below those needed for epidemic control. We assessed whether community mobilisation increased HIV testing, linkage to care, and retention in care over time in intervention relative to control communities.
Achieving access to haemophilia care in low-income and lower-middle-income countries: expanded Humanitarian Aid Program of the World Federation of Hemophilia after 5 years
Authors: Glenn F Pierce, Megan Adediran, Saliou Diop, Amy L Dunn, Magdy El Ekiaby, Radoslaw Kaczmarek, Barbara A Konkle, Steven W Pipe, Mark W Skinner, Leonard A Valentino, Fiona Robinson, Georgios Ampartzidis, Jayson Martin, Assad Haffar
Journal: The Lancet Haematology (2022)
Dietary prevention of ischaemic heart disease.
Authors: I Owens
Journal: BMJ (1980)

provided temptation for use in promotional activities.It is premature to assume that all beta- blocking drugs are equally effective in prevent- ing sudden death and at present it is not known which subgroups of patients might benefit or for how long, and what doses are optimal.Every effort should be made to minimise speculation and over-simplification because of the danger of causing delays in the discovery of relevant mechanisms-or even worse of increasing scepticism and so depriving patients of effective treatment.
A comparative study of cellular diversity between the Xenopus pronephric and mouse metanephric nephron
Authors: Mark E. Corkins, MaryAnne Achieng, Bridget D. DeLay, Vanja Krneta-Stankic, Margo P. Cain, Brandy L. Walker, Jichao Chen, Nils O. Lindström, Rachel K. Miller
Journal: Kidney International (2022)
Vaccine-Associated Uveitis after COVID-19 Vaccination
Authors: Rohan Bir Singh, Uday Pratap Singh Parmar, Francesca Kahale, Aniruddha Agarwal, Edmund Tsui
Journal: Ophthalmology (2022)

To assess the risk of vaccine-associated uveitis (VAU) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and evaluate uveitis onset interval and clinical presentations in the patients.A retrospective study from December 11, 2020, to May 9, 2022, using the Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System.Patients diagnosed with VAU after administration of BNT162b2 (Pfizer-BioNTech, Pfizer Inc/BioNTech SE), mRNA-1273 (Moderna, Moderna Therapeutics Inc), and Ad26.COV2.S (Janssen, Janssen Pharmaceuticals) vaccine worldwide.A descriptive analysis of the demographics, clinical history, and presentation was performed. We evaluated the correlation among the 3 vaccines and continuous and categorical variables. A post hoc analysis was performed between uveitis onset interval after vaccination and age, dose, and vaccine type. Finally, a 30-day risk analysis for VAU onset postvaccination was performed.The estimated global crude reporting rate, observed to expected ratio of VAU in the United States, associated ocular and systemic presentations, and onset duration.A total of 1094 cases of VAU were reported from 40 countries with an estimated crude reporting rate (per million doses) of 0.57, 0.44, and 0.35 for BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively. The observed to expected ratio of VAU was comparable for BNT162b2 (0.023), mRNA-1273 (0.025), and Ad26.COV2.S (0.027). Most cases of VAU were reported in patients who received BNT162b2 (n = 853, 77.97%). The mean age of patients with VAU was 46.24 ± 16.93 years, and 68.65% (n = 751) were women. Most cases were reported after the first dose (n = 452, 41.32%) and within the first week (n = 591, 54.02%) of the vaccination. The onset interval for VAU was significantly longer in patients who received mRNA-1273 (21.22 ± 42.74 days) compared with BNT162b2 (11.42 ± 23.16 days) and rAd26.COV2.S (12.69 ± 16.02 days) vaccines (P < 0.0001). The post hoc analysis revealed a significantly shorter interval of onset for the BNT162b2 compared with the mRNA 1273 vaccine (P < 0.0001). The 30-day risk analysis showed a significant difference among the 3 vaccines (P < 0.0001).The low crude reporting rate and observed to expected ratio suggest a low safety concern for VAU. This study provides insights into a possible temporal association between reported VAU events and SARS-CoV-2 vaccines; however, further investigations are required to delineate the associated immunological mechanisms.
Molecular programs associated with glomerular hyperfiltration in early diabetic kidney disease
Authors: Vidar T.N. Stefansson, Viji Nair, Toralf Melsom, Helen C. Looker, Laura H. Mariani, Damian Fermin, Felix Eichinger, Rajasree Menon, Lalita Subramanian, Patricia Ladd, Roger Harned, Jennifer L. Harder, Jeffrey B. Hodgin, Petter Bjornstad, Peter J. Nelson, Bjørn O. Eriksen, Robert G. Nelson, Matthias Kretzler
Journal: Kidney International (2022)

Hyperfiltration is a state of high glomerular filtration rate (GFR) observed in early diabetes that damages glomeruli, resulting in an iterative process of increasing filtration load on fewer and fewer remaining functional glomeruli. To delineate underlying cellular mechanisms of damage associated with hyperfiltration, transcriptional profiles of kidney biopsies from Pima Indians with type 2 diabetes with or without early-stage diabetic kidney disease were grouped into two hyperfiltration categories based on annual iothalamate GFR measurements. Twenty-six participants with a peak GFR measurement within two years of biopsy were categorized as the hyperfiltration group, and 26 in whom biopsy preceded peak GFR by over two years were considered pre-hyperfiltration. The hyperfiltration group had higher hemoglobin A1c, higher urine albumin-to-creatinine ratio, increased glomerular basement membrane width and lower podocyte density compared to the pre-hyperfiltration group. A glomerular 1240-gene transcriptional signature identified in the hyperfiltration group was enriched for endothelial stress response signaling genes, including endothelin-1, tec-kinase and transforming growth factor-β1 pathways, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. Thus, our analysis reveals molecular pathomechanisms associated with hyperfiltration in early diabetic kidney disease involving putative ligand-receptor pairs with downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells.
Complex in vitro 3D models of digestive system tumors to advance precision medicine and drug testing: Progress, challenges, and trends
Authors: Sheng-Lei Song, Bo Li, Mariana R. Carvalho, Hui-Jin Wang, De-Li Mao, Ji-Tao Wei, Wei Chen, Zhi-Hui Weng, Yang-Chao Chen, Chu-Xia Deng, Rui L. Reis, Joaquim M. Oliveira, Yu-Long He, Le-Ping Yan, Chang-Hua Zhang
Journal: Pharmacology & Therapeutics (2022)